HORIZONS-AMI: A Large Prospective Randomized Trial of DES vs BMS in Patients with STEMI Gregg W. Stone MD Columbia University Medical Center Cardiovascular Research Foundation
Disclosures Gregg W. Stone Research support from The Medicines Company, Boston Scientific and Abbott Vascular
The 1 st Debate: Treatment of Acute Coronary Thrombosis and STEMI rt-pa PTCA
23 Randomized Trials of PCI vs. Lysis N = 7,739 p=0.0002 P<0.0001 P<0.0001 p=0.0002 Death Reinfarction Hemorrhagic stroke Total stroke Keeley, Grines. Lancet 2003;361:13-20
13 RCTs of BMS vs. Balloon PTCA in AMI N=6,922 30 day events Bare metal stents Balloon angioplasty RR [95% CI] RR [95% CI] 0.97 [0.74, P Value Mortality 2.9% 3.0% 0.83 1.27] 0.92 Reinfarction 2.0% 2.2% 0.61 [0.66, 1.27] 0.60 TVR 3.1% 5.1% 0.0001 [0.47, 0.77] 6-12 month events 0.98 [0.79, Mortality 5.1% 5.2% 0.82 1.10] Reinfarction 3.7% 3.9% 0.94 [0.74, 1.20] 0.61 0.62 TVR 11.3% 18.4% <0.0001 [0.55, 0.69] 0 0.5 1 1.5 2 BMS better PTCA better De Luca G et al. Int J Cardiol.. 2007;119:306-9. 9.
Massachusetts State Registry 2-year mortality (propensity adjusted) in 1298 matched pairs (2596 pts) with STEMI at 21 hospitals between 4/03 9/04 Death (adjusted) (%) 30 20 10 2% mortality at 30 days! 3% mortality at 1-year! 1 BMS (n=1298) DES (n=1298) P=0.008 11.6% 8.5% 0 0 30 180 365 730 Days after Initial Procedure Drug-Eluting Stent No. at risk 1298 1289 1250 1227 1213 Cum. incidence (%) 0.7 3.7 5.5 6.5 8.5 Bare-Metal Stent No. at risk 1298 1292 1223 1194 1173 Cum. incidence (%) 0.5 5.8 8.0 9.6 11.6 Mauri L et al. NEJM 2008;359:1330-42
11 DES vs. BMS RCTs in AMI (n=3,607) Death at 12 Months Study DES n/n BMS n/n OR (fixed) 95% CI Weight % OR (fixed) 95% CI DiLorenzo et al 7/180 6/90 10.20 0.57 [0.18, 1.74] BASKET-AMI 6/143 6/74 10.05 0.50 [0.15, 1.60] DEDICATION 16/313 8/313 10.07 2.05 [0.87, 4.87] Diaz de la Llera et al 3/60 2/54 2.65 1.37 [0.22, 8.52] HAAMU-STENT 8/82 4/82 4.79 2.11 [0.61, 7.30] MISSION 2/158 4/152 5.34 0.47 [0.09, 2.63] PASSION 16/310 20/309 25.19 0.79 [0.40, 1.55] SELECTION 1/40 3/40 3.88 0.32 [0.03, 3.18] SESAMI 3/160 6/160 7.81 0.49 [0.12, 2.00] STRATEGY 7/87 8/88 9.70 0.88 [0.30, 2.53] TYPHOON 8/355 8/357 10.34 1.01 [0.37, 2.71] Total (95% CI) 77/1888 75/1719 100.00 4.1% 4.4% Test for heterogeneity: I 2 = 0% Favors DES Favors BMS 0.1 0.2 0.5 1 2 5 10 0.91 [0.66, 1.27] P=0.59 De Luca G et al. Int J Cardiol 2008
11 DES vs. BMS RCTs in AMI (n=3,607) TVR at 12 Months Study DES n/n BMS n/n OR (fixed) 95% CI Weight % OR (fixed) 95% CI DiLorenzo et al 7/180 14/90 8.40 0.22 [0.09, 0.57] BASKET-AMI 10/143 9/74 5.17 0.54 [0.21, 1.40] DEDICATION 16/313 41/313 18.22 0.36 [0.20, 0.65] Diaz de la Llera et al 0/60 3/54 1.71 0.12 [0.01, 2.41] HAAMU-STENT 3/82 8/82 3.61 0.35 [0.09, 1.37] MISSION 5/158 17/152 7.86 0.26 [0.09, 0.72] PASSION 16/310 23/309 10.23 0.68 [0.35, 1.31] SELECTION 2/40 13/40 5.79 0.11 [0.02, 0.52] SESAMI 7/160 20/160 8.96 0.32 [0.13, 0.78] STRATEGY 8/87 21/88 8.88 0.32 [0.13, 0.78] TYPHOON 20/355 48/357 21.16 0.38 [0.22, 0.66] Total (95% CI) 94/1888 217/1719 100.00 Test for heterogeneity: I 2 = 0% 5.0% 12.6% = 7.6% 0.1 0.2 0.5 Favors DES 1 2 5 10 Favors BMS 0.36 [0.28, 0.47] P<0.0001 De Luca G et al. Int J Cardiol 2008
DES in AMI: The TYPHOON Trial Primary Endpoint (TVF*) Through 360 Days TVF (%) 25 20 15 10 5 0 2.8 3.1 SES BMS Routine Angio FU 6.2 4.2 Time (days) 49% P = 0.004 14.3 7.3 0 60 120 180 240 300 360 * Defined as target vessel-related cardiac death, ReMI or ischemia driven TVR Spaulding C et al. NEJM 2006;355:1093-104. 104.
Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset 12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to CABG Primary PCI Medical Rx 3006 pts eligible for stent randomization R 3:1 Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years; angio FU at 13 months
HORIZONS: 30 Day Adverse Events P<0.001 P = 0.90 P = 0.002 *Not related to CABG ** Plat cnt <100,000 cells/mm 3 Stone GW et al. NEJM 2008;358:2218-30 30
HORIZONS: 1-Year All-Cause Mortality 5 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% Mortality (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 4 3 2 1 0 3.1% 2.1% = 1.0% P=0.049 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months 1800 1705 1684 1669 1520 1802 1678 1663 1646 1486 = 1.4% 3.4% Diff [95%CI] = -1.5% [-2.8,-0.1] HR [95%CI] = 0.69 [0.50, 0.97] P=0.029 Stone GW et al. NEJM 2008;358:2218-30 30 Stone GW. TCT 2008
Harmonizing Outcomes with Revascularization and Stents in AMI Primary Medical Rx 193 Primary CABG 62 Deferred PCI 2 Index PCI, not eligible - PTCA only 119 - Stented 220 93.1% of all stented pts were randomized 3602 pts with STEMI R 3:1 R 1:1 3006 pts eligible for stent rand. UFH + GPI (n=1802) Bivalirudin (n=1800) Randomized TAXUS DES N=2257 EXPRESS BMS N=749 18 53 Withdrew Lost to FU 7 27 1 year FU N=2186 (96.9%) N=715 (95.5%)
One-Year All-Cause Mortality 5 TAXUS DES (n=2257) EXPRESS BMS (n=749) Mortality (%) 4 3 2 1 3.5% 3.5% HR [95%CI] = 0.99 [0.64,1.55] P=0.98 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Number at risk TAXUS DES EXPRESS BMS Time in Months 2257 2180 2161 2147 1949 749 716 712 702 648 Stone GW. In press.
Stent Thrombosis (%) 4 3 2 1 0 Number at risk PES BMS Stent Thrombosis (ARC Definite or Probable) Paclitaxel-eluting stents (n=2238) Bare metal stents (n=744) 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months 2238 2123 2098 2079 1885 744 701 694 683 629 Stone GW. In press. HR [95%CI] = 0.93 [0.59,1.47] P=0.77 3.4% 3.2%
Primary Efficacy Endpoint: Ischemic TLR Ischemic TLR (%) Number at risk TAXUS DES EXPRESS BMS 10 9 8 7 6 5 4 3 2 1 0 Diff [95%CI] = -3.0% [-5.1,[ -0.9] HR [95%CI] = 0.59 [0.43, 0.83] P=0.002 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months TAXUS DES (n=2257) EXPRESS BMS (n=749) 2257 2132 2098 2069 1868 749 697 675 658 603 7.5% 4.5% Stone GW. In press.
Binary Analysis Segment Restenosis at 13 Months Patient and Lesion Level Analysis* RR [95%CI] = 0.44 [0.33, 0.57] P<0.0001 RR [95%CI] = 0.44 [0.33, 0.57] P<0.0001 Major 2 endpoint * ITT: Includes all stent randomized lesions, whether or not a stent was implanted, and whether or not non study stents were placed ** Any lesion with restenosis per pt restenosis Stone GW. In press.
Multivariable Predictors of 1-Year 1 TLR (BMS Express patients, N=734) Variable HR (95% CI) P-value Total lesion length 1.03 [1.01, 1.05] 0.002 Baseline RVD 0.22 [0.11, 0.42] <0.0001 Insulin-treated diabetes 3.17 [1.23, 8.18] 0.02 Lesion ulceration 4.08 [1.53,10.88] 0.005 Stone GW. ACC2009.
Multivariable Predictors of 1-Year 1 TLR (BMS Express patients, N=734) Variable Score HR (95% CI) P-value Total lesion length 40 mm 2 5.28 [1.73,16.15] 0.004 Baseline RVD 3.0 mm 1 3.27 [1.63, 6.55] 0.0008 Insulin-treated diabetes 1 3.00 [1.17, 7.66] 0.02 Lesion ulceration 1 3.45 [1.30, 9.16] 0.01 Killip class 2-4 1 2.50 [1.20, 5.20] 0.01 Stone GW. ACC2009.
1-Year TLR According to BMS Risk Score (N=2915) N=946 (32.5%) N=1520 (52.1%) N=449 (15.4%) Stone GW. ACC2009.
Multivariable Predictors of 13 Month In-segment Restenosis (BMS Express patients, N=290) Variable Score HR (95% CI) P-value Total lesion length 40 mm Total lesion length 30 - <40 mm 2 6.64 [1.18,37.46] 0.03 1 3.40 [1.10,10.51] 0.03 Baseline RVD 3.0 mm 1 4.20 [2.18, 8.11] <0.0001 Age 65.0 years 1 1.78 [0.98, 3.24] 0.06 Stone GW. ACC2009.
13 Month In-segment Restenosis According to BMS Risk Score (N=1194) N=296 (24.8%) N=531 (44.7%) N=367 (30.7%) Stone GW. ACC2009.
Stent Selection in STEMI In pts with STEMI undergoing primary PCI, use of TAXUS rather than BMS results in: Comparable rates of stent thrombosis, reinfarction and death through 1 year Significant reductions in TLR, TVR and angiographic late loss and restenosis,, in all lesions except for those at low risk for restenosis Longer term follow-up is required to comprehensively assess the late safety and efficacy profile of DES in STEMI